Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.

Neurofibromas are one of the most characteristic features of neurofibromatosis type 1 (NF1), an inherited autosomal-dominant neurogenetic disorder affecting 1 in 3500 individuals worldwide. These benign tumors mainly consist of Schwann cells (SCs) and fibroblasts. Recent evidence demonstrates that somatic mutations at the NF1 gene are found in neurofibromas, but it has not been demonstrated whether SCs, fibroblasts and/or both cell types bear a somatic loss of NF1. We recently established a cell culture system that allows selective expansion of human SCs from neurofibromas. We cultured pure populations of SCs and fibroblasts derived from 10 neurofibromas with characterized NF1 mutations and found that SCs but not fibroblasts harbored a somatic mutation at the NF1 locus in all studied tumors. Furthermore, by culturing neurofibroma-derived SCs under different in vitro conditions we were able to obtain two genetically distinct SC subpopulations: NF1(-/-) and NF1(+/-). These data strongly support the idea that NF1 mutations in SCs, but not in fibroblasts, correlate to neurofibroma formation and demonstrate that only a portion of SCs in neurofibromas have mutations in both NF1 alleles.

Relapsing polychondritis in childhood--case report and short review.

Relapsing polychondritis (RP) is a disease of unknown etiology and it is characterized by inflammation of the cartilage. While the clinical picture of RP in adults is well described, RP in childhood is poorly documented. We describe a young girl presenting with acute dyspnea, stridor and polyarthritis. The diagnosis of RP was made 2 years after first presentation, when auricular chondritis occurred. Based on a MEDLINE search, reports on RP in childhood were reviewed. The frequency of chondritis and systemic manifestations of RP in children was compared to data in adults and found to be very similar. RP in childhood can be a life-threatening and debilitating disease.

Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.

Long-term culture and characterization of human neurofibroma-derived Schwann cells.

Neurofibromas are benign tumors arising from the peripheral nerve sheath and are a typical finding in neurofibromatosis type 1 (NF1). Schwann cells are the predominant cell type in neurofibromas and thus are supposed to play a major role in the pathogenesis of these tumors. It is not known, however, if NF1 mutations in Schwann cells result in an altered phenotype that subsequently leads to tumor formation. To characterize the biological properties of neurofibroma-derived Schwann cells we developed cell culture techniques that enabled us to isolate Schwann cells from neurofibromas and grow them in vitro for several weeks without significant fibroblast contamination. Neurofibroma-derived Schwann cells were characterized by altered morphology, heterogeneous growth behavior, and increased expression of the P0 antigen while several other features of normal human Schwann cells were retained. We conclude that neurofibroma-derived Schwann cells exhibit a distinct phenotype in vitro but that the observed abnormalities by themselves are insufficient to explain neurofibroma formation. Application of our improved culture conditions makes neurofibroma-derived Schwann cells readily available for further studies to define their role in tumorigenesis in neurofibromatosis type 1.

Multiple intracranial juvenile xanthogranulomas. Case report.

The authors report on an 11-year-old boy in whom proptosis of the eye caused by a benign intraosseous xanthofibroma of the left orbital wall became clinically apparent at the age of 4 years. Two years later he developed bilateral papilledema, at which time computerized tomography and magnetic resonance studies revealed multiple enhancing intracranial lesions. The largest mass was located in the left middle fossa; other lesions were located at the tentorium cerebelli, in both lateral ventricles, near the superior sagittal sinus, and extracranially near the left jugular vein. The mass in the left middle fossa was resected and diagnosed as juvenile xanthogranuloma (JXG). Thirty months later, the patient again became symptomatic, exhibiting behavioral abnormalities and a decrease in mental powers. At that time, the two remaining lesions in both lateral ventricles had grown enough to cause trapping of the temporal horns and raised intracranial pressure. These lesions were successively resected and histopathologically confirmed to be JXGs. However, resection of the second intraventricular lesion was complicated by postoperative bilateral amaurosis, presumably caused by postdecompression optic neuropathy. According to a review of the literature, fewer than 20 patients with JXG involving the central nervous system have been reported. The patient described in this report is the first in whom multiple intracranial JXGs developed in the absence of cutaneous manifestations. Although JXGs are biologically benign lesions, the treatment of patients with multifocal and/or progressive intracranial manifestations is problematic.

End-of-life decisions in neonatal intensive care: physicians' self-reported practices in seven European countries. EURONIC Study Group.

BACKGROUND: The ethical issue of foregoing life-sustaining treatment for newborn infants at high risk of death or severe disability is extensively debated, but there is little information on how physicians in different countries actually confront this issue to reach end-of-life decisions. The EURONIC project aimed to investigate practices as reported by physicians themselves. METHODS: The study recruited a large, representative sample of 122 neonatal intensive-care units (NICUs) by census (in Luxembourg, the Netherlands, and Sweden) or stratified random sampling (in France, Germany, the UK, Italy, and Spain) with an overall response rate of 86%. Physicians' practices of end-of-life decision-making were investigated through an anonymous, self-administered questionnaire. 1235 completed questionnaires were returned (response rate 89%). FINDINGS: In all countries, most physicians reported having been involved at least once in setting limits to intensive care because of incurable conditions (61-96%); smaller proportions reported such involvement because of a baby's poor neurological prognosis (46-90%). Practices such as continuation of current treatment without intensification and withholding of emergency manoeuvres were widespread, but withdrawal of mechanical ventilation was reported by variable proportions (28-90%). Only in France (73%) and the Netherlands (47%) was the administration of drugs with the aim of ending life reported with substantial frequency. Age, length of professional experience, and the importance of religion in the physician's life affected the likelihood of reporting of non-treatment decisions. INTERPRETATION: A vast majority of neonatologists in European NICUs have been involved in end-of-life limitation of treatments, but type of decision-making varies among countries. Culture-related and other country-specific factors are more relevant than characteristics of individual physicians or units in explaining such variability.

Rapid progressive subacute sclerosing panencephalitis in a 2-year-old child with congenital athyreosis.

We present the unique case of a 2-year-old girl with congenital athyreosis who acquired primary measles virus infection at the age of 18 months, coincidentally with an Epstein-Barr virus infection. First neurologic symptoms of subacute sclerosing panencephalitis appeared 5 months later, and the girl died within 6 months after a rapid progressive illness. Factors possibly predisposing to this extraordinary disease course-primary measles virus infection at an early age and lack of evidence for immunodeficiency-are discussed.

Multiple symmetric lipomatosis: an unusual cause of childhood obesity and mental retardation.

Multiple symmetric lipomatosis (MSL), also known as Launois-Bensaude syndrome or Madelung's disease, is a rare disorder predominantly seen in middle-aged male patients. The disorder is characterized by large subcutaneous fat masses distributed around the neck, shoulders, and other parts of the trunk, often associated with nervous system abnormalities. A close relationship to alcoholism, metabolic disturbances and malignant tumours has been observed. Until now, MSL has only been described in adults. We report on the first two children, a 9-year-old girl and a 13-year-old boy, with the characteristic clinical findings of MSL. The girl presented with severe obesity, developmental delay, mild mental retardation, peripheral neuropathy, and latent hypothyroidism. In addition, she had elevated lactate concentrations in blood and cerebral spinal fluid suggesting mitochondrial dysfunction. Biochemical analyses of muscle showed a respiratory chain complex II deficiency. The boy suffered from severe obesity, mild mental retardation and insulin resistant diabetes mellitus. In both children, analyses of the mitochondrial genome did not reveal major deletions nor the MERRF 8344 point mutation. MSL seems to be a new neurometabolic disorder with heterogeneous clinical expression whose pathogenesis is still unknown.

Interdisciplinary treatment in pediatric patients with malignant CNS tumors.

Despite sophisticated surgical methods only a few pediatric CNS tumors can be controlled by operation alone. Therefore multimodality treatment regimens are needed to improve quality of life and survival, which is most important in malignant neoplasms. Since 1998 we have treated 16 children with malignant CNS tumors. All 16 patients have been treated on an interdisciplinary basis and are therefore accompanied by a pediatric neurooncology group consisting of a neurosurgeon, pediatric oncologist, and radiotherapist. Depending on tumor histology, child's age, and extent of surgery, further adjuvant therapy is planned by this group. Newly diagnosed tumors are typically treated by a specific chemotherapy protocol according to a multi-institutional study. In recurrent tumors more individual treatment regimens are considered. Data concerning surgery, adjunctive treatment, complications, and outcome of all patients and four case reports are presented.

CT and MRI of congenital sinonasal ossifying fibroma.

We report a 9-year-old boy with a sinonasal ossifying fibroma, probably congenital, with atypical findings on CT and MRI. CT revealed a soft-tissue density mass in the sphenoethmoidal sinuses, nasal cavity and right maxillary sinus with a few foci of calcification and with remodelling and destruction of the adjacent facial bones. MRI showed high signal on T2- and intermediate signal on T1-weighted images. A thin, partly enhancing outer shell and some nonenhancing septa were visible on contrast-enhanced images. MRI also showed the tumour to extend into the anterior cranial fossa. Subtotal removal was performed. We compare our findings with reports in the literature and discuss the differences from fibrous dysplasia.

MRI abnormalities in neurofibromatosis type 1 (NF1): a study of men and mice.

Hyperintense lesions on T2-weighted MR images of the brain, predominantly located in the basal ganglia, the brainstem and cerebellum, are a frequent finding in patients with neurofibromatosis type 1. Nature and significance of these lesions are still unknown so that the term 'unidentified bright objects' (UBOs) has been introduced to allow an unbiased description. We analyzed brain MRI scans of 31 children with definite diagnosis of neurofibromatosis type 1 according to the NIH criteria. High-intensity lesions on T2-weighted images were present in 86% of the patients. They did not correlate to other MRI findings such as optic pathway gliomas and were not indicative of intellectual impairment. Additionally, brain MR imaging of Nf1 knockout mice was performed to find out if similar abnormalities are present in this animal model. A total of 9 Nf1 knockout mice was examined on a dedicated animal MRI scanner at 4.7 Tesla but no evidence of high-signal intensity lesions on T2-weighted images was found. Therefore, the Nf1 mouse model seems to be unhelpful in providing further insights into the histological basis of hyperintense MRI abnormalities in NF1 patients.

A new leukoencephalopathy with bilateral anterior temporal lobe cysts.

We describe an identical syndrome of cystic leukoencephalopathy in three Turkish children, including two siblings. The neurological findings were noted within the first months of life and include severe intellectual impairment, motor retardation, and spasticity. Magnetic resonance imaging of the brain showed extensive cysts within the anterior temporal lobes, ventricular enlargement and white matter disease. The signal intensities of the cysts' content were identical to those of the cerebrospinal fluid. The patients' screening for known inborn errors of metabolism, especially those characterised by white matter involvement, did not reveal any abnormality. The clinical picture and the magnetic resonance imaging characteristics are unique diagnostic features of a new disease entity so far not described in the literature.

Megalencephaly, mega corpus callosum, and complete lack of motor development: a previously undescribed syndrome.

We report on 3 sporadic cases of in utero onset megalencephaly. Children were born to healthy nonconsanguineous parents after uneventful pregnancies. Head circumferences were just above the 97th centile at birth in 2 patients, 2 cm above the 97th centile in 1 patient, and subsequently increased to 4.5-6.5 cm above the 97th centile at age 5 years. All patients completely lacked motor and speech development and showed very little intellectual progress. There was a distinctive facial aspect with frontal bossing, low nose bridge, and large eyes, but no cutaneous abnormalities and no signs of other organ involvement. Magnetic resonance imaging showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in pachygyric appearance of the cortex. Opercularization was incomplete, and the Sylvian fissures were wide. Somatosensory evoked potentials in 1 patient showed normal latencies of cervical and contracortical potentials but bilaterally increased cortical amplitudes. To the best of our knowledge, no similar case observations have been recorded previously.

Cerebellar mutism syndrome.

Since 1980, a growing number of pediatric patients with mutism following posterior fossa surgery have been recognized. This syndrome typically affects children and in rare cases young adults who become mute one or two days after tumor operation but do not show disturbances of consciousness or language comprehension. The disorder persists for 1 to 4 months. The pathogenesis is still unknown. Of 21 children who underwent surgery for large posterior fossa tumors between 1991 and 1995, 6 developed cerebellar mutism. Histologically the tumors were classified as astrocytoma WHO grade I, astrocytoma WHO grade II and ependymoma WHO grade III in one case and medulloblastoma WHO grade IV in three cases. Besides the clinical course, intraoperative findings and CT or MRI data are evaluated and discussed considering possible etiological hypotheses. Our own experience and also literature reviews suggest that the lesion of the cerebellar hemispheres might be the most important one of multiple factors causing cerebellar mutism. Generally the syndrome is transient. The diagnosis should not delay adjuvant therapy in patients with a malignancy.

Paraneoplastic limbic encephalitis in two teenage girls.

Paraneoplastic neurological disorders represent remote effects of cancer without invasion of tumor cells into the nervous system. Limbic encephalitis is a distinct entity mostly associated with small-cell carcinoma of the lung. We present the cases of two teenage girls who were admitted with clinical symptoms typical for limbic encephalitis. In the course of the disease, they exhibited characteristic evolutionary changes of brain MRI abnormalities. Onset of neurological symptoms and type of underlying neoplasia were different in both patients. In one girl the initial workup led to the diagnosis of nodular sclerosing Hodgkin disease which so far had not caused any symptoms besides the described neurological abnormalities. A diagnostic brain biopsy showed inflammatory changes and excluded invasion of malignant cells into the central nervous system. The other patient had been diagnosed with a small cell carcinoma of the ovary several months before neurological and brain MRI abnormalities were observed. This is the first report in which clinical picture, evolution of MRI abnormalities, and--in one case--characteristic neuropathological changes are suggestive of paraneoplastic limbic encephalitis in two adolescent girls.